Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo

Background: Psoriasis is one of the most frequent skin diseases world-wide. The disease impacts enormously on affected patients and poses a huge financial burden on health care providers. Several lines of evidence suggest that the nuclear hormone receptor peroxisome proliferator activator (PPAR) beta/delta, known to regulate epithelial differentiation and wound healing, contributes to psoriasis pathogenesis. It is unclear, however, whether activation of PPAR beta/delta is sufficient to trigger psoriasis-like changes in vivo. Methodology/Principal Findings: Using immunohistochemistry, we define the distribution of PPAR beta/delta in the skin lesions of psoriasis. By expression profiling, we confirm that PPAR beta/delta is overexpressed in the vast majority of psoriasis patients. We further establish a transgenic model allowing inducible activation of PPAR beta/delta in murine epidermis mimicking its distribution in psoriasis lesions. Upon activation of PPAR beta/delta, transgenic mice sustain an inflammatory skin disease strikingly similar to psoriasis, featuring hyperproliferation of keratinocytes, dendritic cell accumulation, and endothelial activation. Development of this phenotype requires the activation of the Th17 subset of T cells, shown previously to be central to psoriasis. Moreover, gene dysregulation in the transgenic mice is highly similar to that in psoriasis. Key transcriptional programs activated in psoriasis, including IL1-related signalling and cholesterol biosynthesis, are replicated in the mouse model, suggesting that PPAR beta/delta regulates these transcriptional changes in psoriasis. Finally, we identify phosphorylation of STAT3 as a novel pathway activated by PPAR beta/delta and show that inhibition of STAT3 phosphorylation blocks disease development. Conclusions: Activation of PPAR beta/delta in the epidermis is sufficient to trigger inflammatory changes, immune activation, and signalling, and gene dysregulation characteristic of psoriasis.